Michael Juhnke

Generation of wear during the production of drug nanosuspensions by wet media milling.

Wet media milling is an established technique for the commercialized top-down production of nanoparticulate drug suspensions. These drug nanosuspensions can be transferred into the related drug products, like capsules, tablets and injectables. The generation of wear during stirred media milling of a drug compound was investigated for grinding media made from yttrium stabilized zirconia. Drug compound and drug nanosuspension were characterized initially by their mechanical and rheological properties. The generation of wear from grinding media has been investigated simultaneously with the reduction of drug particle size by evaluating several grinding media supplier and diameter as well as process parameters stirrer tip speed and specific energy input. Grinding media quality and process parameters were identified with strong impact on the amount of generated wear and on drug particle size distribution. Wear from grinding media characterized by elemental zirconium and yttrium could be significantly minimized by operating with the favored grinding media quality and with optimal stirrer tip speed and specific energy input. Wear debris, respectively wear particles from grinding media, were identified with respect to morphology and particle size. Finally, the overall contamination by raw materials and by wear during processing characterized by elemental iron, silicium, yttrium and zirconium as well as the mean size of contamination particles are presented for selected drug nanosuspensions.

Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling.

The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process.

Impact of Formulation Properties and Process Parameters on the Dispensing and Depositioning of Drug Nanosuspensions Using Micro-Valve Technology

Flexible manufacturing processes with continuously adjustable dose strengths are considered particularly innovative and interesting for applications in personalized medicine, continuous manufacturing, or early drug development. A piezo-actuated micro-valve has been investigated for the dispensing and depositioning of drug nanosuspensions onto substrates to facilitate the manufacturing of solid oral dosage forms. The investigated micro-valve has been characterized regarding dispensing behavior, mass flow, accuracy, and robustness. The amount of dispensed drug compound during 1 dispensing event could be continuously adjusted from a few micrograms to several milligrams with high accuracy. Fluid properties, dispensing parameters of the micro-valve, and the resulting steady state mass flow could be correlated adequately for low-viscous drug nanosuspensions. High-speed imaging was used to investigate the dispensing behavior of the micro-valve regarding the evolution of the dispensed drug nanosuspension after ejection from the nozzle and the behavior during impact on flat and dry solid substrates. The experimentally determined breakup length of the dispensed liquid jet could be correlated with a semiempirical equation. From image sequences of the jet impact, We-Re phase diagrams could be established, providing a profound understanding and systematic guidance for the controlled depositioning of the entire dispensed drug nanosuspension onto the substrate.

Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology

Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior.